A zoonosis is an infectious disease that is transmitted between species (sometimes by a vector) from animals other than humans to humans or from humans to other animals. Of the more than 1,400 pathogens known to infect humans, greater than 60% of them are zoonotic (see, e.g., Taylor et al. (2001) Philosophical Transactions of the Royal Society B 356(1411):983-9).
Brucellosis is a bacterial zoonosis of global magnitude. The causative agent is a gram negative alpha proteobacterium, Brucella, that infects a wide range of mammals, including essentially all economically important domestic mammals and many wild species. In humans, untreated brucellosis is a long lasting disease characterized by recurrent fever episodes and clinical manifestations that include spondylitis, severe headaches, joint or abdominal pain, endocarditis, and meningoencephalitis. In severe non-treated cases brucellosis can cause death (Moreno E, Moriyón I (2006). In: Dworkin M, Falkow S, Rosenberg E, Schleifer K H, Stackebrant E, editors. Vol. 5. Part 1, section 3.1. The Prokaryotes. New York: Springer-Verlag. pp. 315-456; Ariza J, et al. (2007) PLOS medicine 4:1872-1878; Pappas G, et al. (2005) New Engl J Med. 352:2325-2336).
Q-fever is a zoonotic disease caused by infection with Coxiella burnetii, an obligate intracellular pathogenic bacterium that affects humans and other animals. This organism is found in cattle, sheep, goats and other domestic mammals, including cats and dogs. The infection results from inhalation of a spore-like small cell variant, and from contact with the milk, urine, feces, vaginal mucus, or semen of infected animals; ticks may also transmit the bacteria. Although most persons with acute Q fever infection recover, others may experience serious illness with complications that may include pneumonia, granulomatous hepatitis, myocarditis (inflammation of the heart tissue), central nervous system complications, and death. Pregnant women who are infected may be at risk for pre-term delivery or miscarriage.
Lyme disease, is a zoonotic disease caused by bacteria belonging to the genus Borrelia. Lyme disease is transmitted to humans by the bite of infected ticks belonging to a few species of the genus Ixodes (“hard ticks”). If Lyme disease is not detected and treated while early symptoms are present, or if symptoms are not present, the infection may affect the skin, joints, nervous system, and heart within weeks to months after the initial infection. Late disseminated infections may occur and result in joint inflammation, numbness and tingling in the hands, feet, or back, severe fatigue, partial facial nerve paralysis, neurologic changes, including problems with memory, mood, or sleep, and sometimes problems speaking.
Detection of the zoonotic bacterium Brucella by culture remains the gold standard for diagnosis (Moreno E, Moriyón I (2006). In: Dworkin M, Falkow S, Rosenberg E, Schleifer K H, Stackebrant E, editors. Vol. 5. Part 1, section 3.1. The Prokaryotes. New York: Springer-Verlag. pp. 315-456). These methods are slow, and can require weeks to detect bacterial colonies. Further complicating this approach is that the bacteria are present in readily available body fluids intermittently at best. Diagnosis has therefore depended primarily on serology, mostly the detection of circulating immunoglobulins reactive against bacterial LPS and the closely related native hapten (NH) polysaccharides (Moreno E, Moriyón I (2006). In: Dworkin M, Falkow S, Rosenberg E, Schleifer K H, Stackebrant E, editors. Vol. 5. Part 1, section 3.1. The Prokaryotes. New York: Springer-Verlag. pp. 315-456; Cutler S J, et al. (2005) J Appl Microbiol 98:1270-1281). Early in disease, however, antibodies are not always generated or their titers may be intermittent (Baldi P C, et al. (2001) Scand J Infect Dis 33:200-205), hampering early diagnosis.
Furthermore, with respect to Brucella, antibodies against Brucella LPS may also cross react with the LPS of other bacteria, such as Vibrio cholera, and some Yersinia and Salmonella serotypes, resulting in false positives (Moreno E, Moriyón I (2006). In: Dworkin M, Falkow S, Rosenberg E, Schleifer K H, Stackebrant E, editors. Vol. 5. Part 1, section 3.1. The Prokaryotes. New York: Springer-Verlag. pp. 315-456; Baldi P C, et al. (2001) Scand J Infect Dis 33:200-205). Antibodies against alternative Brucella antigens have been evaluated as serological diagnostic markers but with uncertain results (Rolan H G, et al. (2008) Clin Vaccine Immunol 15: 208-214; Contreras-Rodriguez A, et al. (2006) FEMS Immunol Med Microbiol 48:252-256) since it appears that the alternative antigens tend to induce lower immunoglobulin titers than the highly immunogenic LPS. Currently none of the alternative antigens are used for diagnosis of brucellosis.
The gold standard for diagnosis of Lyme Disease is serology, detection of host antibodies reactive to Borrelia proteins. Antibody titers typically do not develop in the first 2 weeks of disease, neccessitating diagnosis to be done based on the non-specific clinical symptoms and the likelihood of exposure to ticks. Furthermore, the accuracy of the test is low on the order of 60% in the US, and less than that in Europe (Robertson J and al. 2000. J Clin Microbiology. 38(6): 2097-2102. Nelson K, Masters C. 2007. Infectious Disease Epidemiology: Theory and Practice. 2nd Ed. Jones and Bartlett Publishers. Chapter 25: Lyme disease. P. 1063-1086).
Serology is also the gold standard for diagnosis of Q-fever. Analysis of two samples taken 2-4 weeks apart is recommended. The reason for this is that the antibody titer for this disease also does not develop immediately after infection, and since the Q fever pathogen is endemic in most areas of the world, a significant subset of the population already has Q fever reactive antibodies from prior exposure (Fournier P E, Marrie T J, Raoult D. 1998. J Clin Microbiol. 36(7): 1823-1834).
PCR methods have also been evaluated as direct diagnostics (Baldi P C, et al. (2001) Scand J Infect Dis 33:200-205; Debeaumont C, et al. (2005) Eur J Clin Microbiol Infect Dis 24:842-845; Casañas M C, et al. (2001) Eur J Clin Micribiol Infect Dis 20:127-131; Elfaki M G, et al. (2005) Med Sci Monit 11:MT69-74). PCR offers considerable improvement in detection speed over culture methods, and has been used to distinguish bacterial species and strains (Baldi P C, et al. (2001) Scand J Infect Dis 33:200-205). Although faster, PCR is less sensitivity as a diagnostic than culture methods (Baldi P C, et al. (2001) Scand J Infect Dis 33:200-205; Elfaki M G, et al. (2005) Med Sci Monit 11:MT69-74).
The current approaches for diagnosis, therefore, rely primarily on products of the host's immune system or on the growth of viable pathogens in culture. Each approach has limitations that can translate into false negative diagnoses. Accordingly, there is a need in the art for novel biomarkers of zoonotic infections, such as Brucella, Coxiella burnetii, and Borrelia infection.